Session S83.2

Relevance of the KCNH2 Protein Stoichiometry to Pathological Conditions Underlying QT Abnormality

C Wang*, P Beyerlein, G Petznick, A Krause,
CD Nugent, W Dubitzky

University of Ulster
Coleraine, Northern Ireland, UK

Genetic defects in the KCNH2 gene are a primary cause of unstable cardiac ventricular repolarization. Due to the complicated tetrameric properties governing the coexpression of the wide-type (WT) KCNH2 gene and its mutant counterpart, knowledge about the relevance of the stoichiometry to various pathological conditions responsible for the QT abnormality are still very limited. The aim of our current work has been to assess the functional implications of the stoichiometric properties.
We have developed the homomeric kinetic models for both the KCNH2 channel and its mutant counterpart with genetic defects in the C-terminus, in addition to a heteromeric model for the coexpressed product. Taking into account the heterologous expression of WT and the mutated KCNH2 in the HEK cells, we incorporated defined deterministic and stochastic tetramerizations into the Luo-Rudy dynamic model.
In comparison with homomeric WT channels, homomeric mutated channels showed a propensity to develop a shorter action potential duration (APD). Our experiments demonstrated that the coexistence of two kinds of homomeric channels in equal amounts resulted in a shorter APD. In addition, our experimentations demonstrated that as a consequence of the interplay between trafficking deficiency and altered kinetics a random tetramerization of WT and mutants resulted in a marked prolongation of APD whereas the coassembly of WT and its mutant in a 2:2 configuration generated only an intermediate level of delayed action potential repolarization. The data generated predict that the frameshift mutations in the C-terminus are responsible for a moderately severe phenotype, being consistent with the clinical presentations observed in the patients.
In conclusion our study associated the pathophysiological conditions to their underlying stoichiomteric properties. These results suggest that stoichiometry of the KCNH2 channel protein complex may be a substrate for variable genetic penetrance and expressivity in long QT syndrome.

(Abstract Control Number: 114)